Pharmaceuticals which enhance neurotransmission of serotonin (5-HT) are useful for the treatment of many psychiatric disorders, including depression and anxiety. The first generation of non-selective serotonin-affecting drugs operated through a variety of physiological functions which caused them to possess numerous undesired side-effects. The more recently prescribed drugs, the selective serotonin reuptake inhibitors (SSRIs), act predominately by inhibiting 5-HT, which is released at the synapses, from being actively removed from the synaptic cleft via a presynaptic serotonin transport carrier. Since SSRIs require several weeks before they exert their full therapeutic effect, this 5-HT blockade mechanism cannot fully account for their therapeutic activity. It is speculated that this two week induction, which occurs before a full antidepressant effect is observed, is due to the involvement of the 5HT1 A autoreceptors which suppress the firing activity of 5-HT neurons, causing a dampening of the therapeutic effect. Studies suggest that after several weeks of SSRI administration, a desensitization of the 5-HT autoreceptors occurs allowing a full antidepressant effect in most patients (see, e.g., LePaul et al., Arch. Pharmacol., 352:141 (1995)). Hence, it is believed that overriding this negative feedback by using 5 HT1A antagonists would potentially increase and accelerate the clinical antidepressant response. Recent studies by Artigas et al., Trends Neurosci., 19:378-383 (1996) suggested a combination of 5-HT1A activity and inhibition of 5-HT uptake within a single molecular entity can achieve a more robust and fast-acting antidepressant effect.
The present invention relates to a new class of molecules which have the ability to act at the 5-HT1A autoreceptors and concommitantly with the 5-HT transporter. Such compounds are therefore potentially useful for the treatment of depression as well as other serotonin disorders.
U.S. Pat. No. 5,468,767 discloses a series of substituted indoles of the following formula useful for the treatment of disorders associated with dysfunction in serotonergic neurotransmission, including depression. ##STR2##
wherein:
R.sub.1 is hydrogen or C.sub.1-4 alkyl; and PA1 R.sub.2 is C.sub.1-4 alkyl or (CH.sub.2).sub.p Ar. PA1 R is hydrogen or alkyl, PA1 R.sub.1 and R.sub.2 are each mono or bicyclic aryl or heteroaryl radicals; PA1 R.sub.3 is hydrogen, alkyl, or a spirocycloalkyl group; and PA1 n is 1 or 2; and m is 1 or 3. PA1 R.sub.1 is aryl; 2-, 3- or 4 pyridinyl; 2-, 4- or 5-pyrimidinyl; 2-pyrazinyl; 2- or 3-thienyl; 2- or 3-furanyl; or 2-, 4- or 5-thiazolyl; PA1 m is zero or an integer from 1 to 2; PA1 R.sup.2 is ##STR5## PA1 n is zero or an integer of 1 to 4. PA1 R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are, independently, hydrogen, halogen, alkoxy, or carboxamide; PA1 R.sub.5 is hydrogen, halogen, CF.sub.3, CN, carbamide, or alkoxy; and PA1 X is (CH.sub.2).sub.n or a 4-6-membered carbocyclic ring, wherein n is an integer of 2 to 4; PA1 R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are, independently, hydrogen or alkoxy; PA1 X is (CH.sub.2).sub.n or a 6-membered carbocyclic ring, wherein n is an integer of 2 to 3; or PA1 3-[(1,4-cis)-4-(7-Methoxy-3,4-dihydro-1H-isoquinolin-2-yl)-cyclohexyl]-1H-i ndole-5-carbonitrile; PA1 3-[(1,4-trans)-4-(7-Methoxy-3,4-dihydro-1H-isoquinolin-2-yl)-cyclohexyl]-1H -indole-5-carbonitrile; PA1 3-[(1,4-cis)-4-(8-Methoxy-3,4-dihydro-1H-isoquinolin-2-yl)-cyclohexyl]-1H-i ndole-5-carbonitrile; PA1 3-[(1,4-trans)-4-(8-Methoxy-3,4-dihydro-1H-isoquinolin-2-yl)-cyclohexyl]-1H -indole-5-carbonitrile; PA1 3-[(1,4-cis)-4-(6-Methoxy-3,4-dihydro-1H-isoquinolin-2-yl)-cyclohexyl]-1H-i ndole-5-carbonitrile; PA1 3-[(1,4-trans)-4-(6-Methoxy-3,4-dihydro-1H-isoquinolin-2-yl)cyclohexyl]-1H- indole-5-carbonitrile; PA1 3-[(1,4-cis)-4-(5-Methoxy-3,4-dihydro-1H-isoquinolin-2-yl)-cyclohexyl]-1H-i ndole-5-carbonitrile; PA1 3-[(1,4-trans)-4-(5-Methoxy-3,4-dihydro-1H-isoquinolin-2-yl)-cyclohexyl]-1H -indole-5-carbonitrile; PA1 3-[(1,4-cis)-4-(3,4-Dihydro-1H-isoquinolin-2-yl)-cyclohexyl]-1H-indole-carb onitrile; PA1 3-[(1,4-trans)-4-(3,4-Dihydro-1H-isoquinolin-2-yl)-cyclohexyl]-1H-indole-ca rbonitrile; PA1 2-[3-(5-Fluoro-1H-indol-3-yl)-propyl]-5-methoxy-1,2,3,4-tetrahydroisoquinol ine; PA1 2-[3-(5-Fluoro-1H-indol-3-yl)-propyl]-6-methoxy-1,2,3,4-tetrahydroisoquinol ine; and PA1 2-[3-(5-Fluoro-1H-indol-3-yl)-propyl]-1,2,3,4-tetrahydroisoquinoline;
WO 9415928 discloses reports a series of piperazine derivatives of the following formula for the treatment of CNS disorders, including depression. ##STR3##
wherein:
WO 93/10092 discloses a series of substituted cyclohexenes of the following formula for the treatment of dopaminergic disorders. ##STR4##
wherein: